The Good Prognosis and Positive Response to the Therapy of Patients with Two Unrelated Clones Del(5q) and Trisomy 8 Does Not Differ to That of the 5q- Syndrome. This Is in Contrast to the Bad Prognosis of Patients with the Same Chromosomal Aberrations in One Clone

Introduction

In 2009, we published an analysis of 68 patients with isolated del(5q), of which 43 fulfilled the criteria of 5q- syndrome (5q- sy). Among these patients (pts), we found 6 pts who had, in addition to the del(5q) clone an unrelated clone with trisomy 8. Since then, we have found another 6 biclonal pts. We present the clinical and cytogenetic data of these 12 pts, which we compare to the findings of typical 5q- sy pts. As a point of interest, we further present the data of 5 pts with the same two chromosomal abberations in one clone.

Clinical data

The comparison of clinical data between pts with two unrelated clones 5q- and +8 and pts with typical 5q- sy did not reveal fundamental differences. All 12 patients are women. The median age is 57, compared to 65 years in our 5q- sy pts. The patients had macrocytic anemia, normal or elevated platelet counts, typical unlobulated megakaryocytes in all cases, and myeloblasts of less than 3%.

Cytogenetic data

The patients were repeatedly examined with the method of conventional G banding and I-FISH (interphase fluorescence in situ hybridization). I-FISH in particular gives reliable results and accurately illustrates the size ratio of both clones. In 11 pts the 5q- clone was always greater, with values ranging from 24.0% to 70.8% (median 46,7%), whereas the +8 clone values ranged from 4.5% to 47.0% (8,7%). In just one patient the +8 clone was nearly twice as high (40.1%) as the del(5q) clone (22.0%). During the first examination of one patient, the I-FISH results for +8 clone were under cut-off value (2%). Only after 3 years was the +8 clone 4.8%, after 5years it reached 9.5%. Repeated cytogenetic examinations are recommended.

Survival data

Since the date of diagnosis the survival length of our 12 pts ranges from 2 to 18 years. 10 pts are alive. One polymorbid patient died after 6 years from non-hematological causes. The other patient had a predominance of trisomy 8 clone (see above). After two years she started to be thrombocytopenic and leukopenic, had repeated infections and died in sepsis. Retrospective examination of the TP53 mutation was negative. The poor prognosis of this patient cannot be attributed to the prevalence of +8 clones, because 3 months prior to the patient’s death, the cytogenetic examination showed a predominence of del(5q) clone (76.5%) over +8 clone (7.2%). Nevertheless, it is necessary to pay close attention to clone size.

Therapy

The patient with 18 years survival was repeatedly and successfully treated with immunosuppressive drugs (cyklosporin A and Prednison), which subsequently halve both clone sizes. At present, the patient is the only one who transformed into RAEB2. Three patients responded to lenalidomid with hematological remission. In one of these cases, after 6 months the 5q- clone decreased from 40.0% to 4.0% and +8 clone increased from 14.0% to 19.0%.

Comparison

We conducted a comparison of our biclonal pts to 5 pts with both chromosomal aberrations in one clone. All had the same percentage of both aberrations. The 5 pts consisted of 4 women and 1 man. They are older than the biclonal pts. Four of them have macrocytic anemia. Three pts have typical unlobulated MGC, and one patient has thrombocythemia, while the rest are thrombocytopenic. The main difference from the biclonal pts is in the type of MDS and bad prognosis. All of them rapidly transformed into RAEB 2. After transient successful treatment 3 patients relapsed and died from AML. Survival was 1 to 3 years. One patient survives in hematological remission after 18 cycles of Vidaza.

Conclusion

Patients with two unrelated clones, with greater del(5q) and smaller trisomy 8 clones, do not differ in prognosis, laboratory finging or in reaction to the immunomodulatory therapy from patients with typical 5q- sy. Therefore, such patients could be diagnosed as subtypes of the 5q- sy. One patient with the prevalence of +8 clone had the shortest survival. The bad prognostic significance of the +8 clone prevalence over 5q- clone demands observation of further similar cases. In the treatment of biclonal pts, it is possible to try immunosuppressive therapy, which is recommended for MDS pts with trisomy 8. For patients who are being treated with lenalidomide there persists an important question about whether the decrease of 5q- clone may worsen a patient’s prognosis. Patients with both chromosomal aberrations in one clone can be considered as an entirely distinct group with poor prognosis.

Grants: NT/13836; PRVOUK-P27/LF1/2.